The overarching goal of this competitive renewal application is to examine the pleiotropic effects of arteriosclerosis (AS), on brain structure and function, either alone or in combination with Alzheimer disease (AD). We propose a prospective, longitudinal study of a convenience sample (231 current + 276 new = 507 subjects), selected using the Framingham cardiovascular risk profile (FCRP) to ensure representation of subjects ranging from little to severe arteriosclerosis (AS). The PPG includes 4 Cores (Administrative, Clinical, Imaging, and Pathology) and 4 Projects. Project 1 (Reed &Jagust) will use amyloid imaging (Pittsburgh Imaging B [PIB] compound) to identify in vivo a cohort of subjects representing the full spectrum of AS, with minimal AD pathology. Project 2 (Weiner, DeCarli, and Singh) will determine the extent to which arteriosclerosis (AS) is associated with changes of brain perfusion and volume and integrity of gray matter (GM) and white matter (WM) and the extent to which these associations relate to AD- vs. CVD-pathology. .Project 6 (Zarow &Vinters) seeks to improve the clinical diagnosis of hippocampal sclerosis and to clarify its pathogenesis. Project 7 (Chui &Mungas) will test the overarching hypothesis using data obtained in the Clinical, Imaging, and Pathology Cores. The PPG has the following major specific aims: 1. To clarify associations between AS and AD, by determining the relationship between AS and amyloid imaging, using the Pittsburgh Imaging B compound (PIB). 2. To improve the diagnosis of vascular cognitive impairment, by characterizing the cross-sectional and longitudinal behavioral, structural and functional phenotype of persons who are PIB negative 3. To clarify the pathogenic significance of decreased cerebral perfusion by correlating MR perfusion with longitudinal changes in cortical gray matter and white matter 4. To improve our understanding of brain behavior relationships, by correlating executive and memory function with anatomically-defined changes in white matter fractional anisotropy, perfusion and GM. 5. To clarify the pathogenesis of hippocampal sclerosis, by comparing immuno-labelling of proteins associated with ischemic and degenerative pathways. 6. To improve the clinical diagnosis of hippocampal sclerosis, based on cross-sectional and longitudinal analyses of risk factors, cognitive performance, MRI. 7. To model the magnitude of direct and diffuse effects of AS on the brain, apart from stroke and AD. 8. To explore whether diffuse brain effects of AS are mediated by decreased perfusion, inflammatory or other metabolic abnormalities.